Brüstle and colleagues tested the ability of lymphocytes to develop into Th17 cells by treating naïve (CD4+CD62L+) Th in culture for 3 days with anti-CD3 and anti-CD28 to stimulate Th0 differentiation. Some cultures also received (1) IL12 and anti-IL4 to stimulate Th1, or (2) IL4 and anti-IFNgamma to stimulate Th2, or (3) anti-IL4, anti-IFNgamma, TGFbeta, IL6, IL1beta, TNF, and IL23 to stimulate Th17. Cells were then restimulated and analyzed by intracellular staining. They found that IRF4-deficient cells differentiate normally into Th1 cells, contradicting an earlier report by the senior author [they attribute the difference to using specific-pathogen-free mice], but not into Th2 cells, as previously reported. They also found that IRF4-deficient cells did not differentiate into Th17 cells. IRF4 is from a family of transcription factors that are required for the production of interferons alpha and beta as well as innate immunity (TLR) signaling and T helper cell differentiation. Mixing cells from normal 'wild-type' (WT) and deficient mice (IRF4-/- also CD45.2+) demonstrated that the defect was intrinsic to the Th17 cell lineage and not due to suppression (figure 1c shown).They made several other, interesting observations and pursue the IRF4 pathway, finding that the transcription factor RORgamma, also previously reported to be required for Th17 cells, is largely dependent on IRF4. They also showed that TGFbeta-induced FoxP3, a marker of regulatory T cells, is only weakly suppressed by IL6 in IRF4-deficient cells, suggesting that this alternative differentiation pathway may explain the failure of Th17 to develop.Brüstle A, Heink S, Huber M, Rosenplänter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M. “The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4” Nat Immunol. 2007 Sep;8(9):958-66

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